: Lipoprotein lipase (LPL) is a multifunctional enzyme which plays a rate-limiting role in both the hydrolysis of circulating triglyceride-rich lipoprotein (chylomicron and VLDL) triglycerides and the delivery of lipolysis products to tissue for utilization. Predominant tissues which synthesize and secrete LPL include muscle and adipose tissue wherein fatty acids are oxidized or stored as triglyceride, respectively. Although LPL is regulated by hormones, nutrients and changes in body weight, increasing evidence support divergent regulation of LPL in muscle and adipose tissue. This is particularly apparent for cAMP which decreases LPL activity, mRNA and gene transcription in adipose cell but increases LPL activity and mRNA in cardiac muscle. In obesity, fasting LPL is elevated in adipose tissue but reduced in muscle. Moreover, following weight reduction and ioscaloric maintenance of the reduced-obese state, the responsiveness of the adipose tissue lipase to insulin and mixed meals increases. In reduced-obese rodents, even greater changes in adipose tissue LPL occur, but cardiac muscle LPL falls even further. These tissue-specific change in LPL suggest a mechanism by which triglyceride-rich lipoprotein triglyceride fatty acids can be partitioned and body weight maintained. It is the purpose of this continuing application to dissect tissue-specific mechanisms of LPL regulation, with an emphasis on the physiology and pathophysiology of LPL regulation by cAMP. In studies which will extend from the level of the LPL gene to the bedside, investigations will focus on these hypotheses that: 1) isoproterenol infused intravenously will decrease adipose tissue LPL activity, mass and mRNA, but increase muscle LPL activity, mass and mRNA in rats and humans; 2) in obese humans and rats, and more so following weight reduction and isocaloric maintenance of the reduced-obese state, that muscle LPL activity, mass and mRNA will be reduced and less responsive to isoproterenol than in normal weight controls; and in addition, in reduced-obese humans, insulin will decrease muscle LPL more than before weight reduction, and more than in normal weight controls; and 3) OTF-1, the ubiquitous octameric nuclear binding factor, and cAMP will be important regulators of adipose and muscle cell LPL gene expression; and, that divergent regulation of LPL gene expression in adipose cells and muscle cells by cAMP will be related to a tissue-specific factor which differentially regulates LPL gene transcription. Overall, these studies should provide new insights into tissue-specific fuel metabolism which may ultimately result in novel strategies to prevent obesity or sustain the reduced-obese state.